title: The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome.
abstract: BACKGROUND
  Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury.
  
  
  METHODS
  We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI.
  
  
  RESULTS
  In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury.
  
  
  CONCLUSIONS
  It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.
authors.affiliation: 1] Department of HPB Surgery, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK [2] Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Robinson
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
authors.forename: D M
authors.initials: DM
authors.lastname: Manas
authors.forename: F
authors.initials: F
authors.lastname: Oakley
authors.forename: J
authors.initials: J
authors.lastname: Mann
authors.forename: S A
authors.initials: SA
authors.lastname: White
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D002955:Leucovorin / Q000009:adverse effects / Q000494:pharmacology; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008533:Megakaryocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D013154:Spleen / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D024042:Collagen Type I; D009944:Organoplatinum Compounds; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D002955:Leucovorin; D005472:Fluorouracil